CA1320131C - Aqueous pharmaceutical preparation containing 11.beta.-hydroxy steroids - Google Patents

Aqueous pharmaceutical preparation containing 11.beta.-hydroxy steroids

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Publication number
CA1320131C
CA1320131C CA000588137A CA588137A CA1320131C CA 1320131 C CA1320131 C CA 1320131C CA 000588137 A CA000588137 A CA 000588137A CA 588137 A CA588137 A CA 588137A CA 1320131 C CA1320131 C CA 1320131C
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CA
Canada
Prior art keywords
cyclodextrin
steroid
beta
water
solubility
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CA000588137A
Other languages
French (fr)
Inventor
Gerrit J Brinks
Johannes G. J. Egberink
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Akzo NV
Original Assignee
Akzo NV
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Publication date
Application filed by Akzo NV filed Critical Akzo NV
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Publication of CA1320131C publication Critical patent/CA1320131C/en
Anticipated expiration legal-status Critical
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Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B82NANOTECHNOLOGY
    • B82YSPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nanotechnology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Pain & Pain Management (AREA)
  • Biophysics (AREA)
  • Rheumatology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)

Abstract

ABSTRACT
Aqueous pharmaceutical preparation The present invention relates to a new pharmaceutical preparation for local application comprising an aqueous solution of 11.beta.-hydroxy-16.alpha.,17.alpha.,21-trimethyl-.DELTA.1,4-pregnadiene-3,20-dione and a .beta.-cyclodextrine derivative.

Description

~3~91~

Aqueous ~harmaceutical preParation The present invention relates to a new pharmaceuti-cal preparation for local application comprising an aqueous solution of ll~-hydroxy~ ,17a,21-trimethyl-1~4-pregnadiene-3,2O-dione (hereinafter called Org 6216 or the Steroid) and a ~-cyclodextrine derivative.
More particularly the said new composition is par-ticularly useful for ophthalmolo~ical purposes, viz. for the treatment of infections in or at the eyes~
In general, ll~-hydroxy steroidæ (corticosteroids) including the Steroid are known for their potent local anti-inflammatory activity, see for example US patent : 3,947,478. Moreover, the Steroid did not expose any significant systemic effect when administered locally.
However, it is also generally known that most cor-ticosteroids when applied to the eyes are held responsi-ble for an unacceptable increase of the intra ocular pressure (I.O.P.) which render ~hem absolutely unsuit-~: able for any ~phthalmological application. Fortunately, ~ however, it was recently found that contrary t~ other : corti~osteroids the Steroid ~id not increase I.O.P., so that also an ophthalmological application of the Steroid could he considered.

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132~31 The Steroid, however, has one significant drawback which hitherto blocked virtually any practical applica-tion namely its extremely poor solubility in aqueous systems.
For local application in the form of injection preparations, eye-drops, ear-drops, nose-sprays or the like the desired concentration of the Steroid in water could not be sbtained. For topical application in the form of a gel, foams, cream or ointment (on water basis) large amounts of the Steroid were necessary in order to have very small amounts penetrated ~hrough the skin.
In general it is known that ~,~ and r-cyclodextrins may form in~lusion complexes with various organic or inorganic compounds and as a result may increase the solubility of these compounds. See e.g. the review article of Saenger in Angewandte Chemie Int. Ed. 19, 344 (198~).
It is Applicant's own experience an~ supported by literature data that the solubility of a compound in water may increase very roughly by a factor 2-500 provided said compound is able to ~orm an inclusion-complex with one of the cyclodextrins.
The Steroid, however, would not benefit from such increase because its original solubility in water of ap-proximately 5x10-4 mg/ml would most ideally increase at most up to a level of about 0,1 mg/ml which is still in-sufficient for local administration o~ the Steroid in general and more in particular for ophthalmological ap-plication. Practical solubility tests carried out with ~,~ and r-cyclodextrin only confirmed this expectation.
Surprisingly, however, it was found that an inclusion complex formed between the Steroid and 2,6-dimethyl-~-cyclodextrin increased the solubility of the Stèroid in water from the original level of 5xlO 4 mg/ml up to a level o~ about 10 mg~ml, which means an increase of the solubility with the unexpectedly high factor of 10.000.

Thi6 increase of the Steroid's solubility in water renders a practical application of the Steroid possible in pharmaceutical preparations for local administration and especially in ophthalmological preparations.
The present invention therefore encompasses a phar-maceu~ical preparation for local administration, and especially an ophthalmological preparation comprising an aqueous solution of ll~-hydroxy-16~,17~,21-trimethyl-4_ pregnadiene 3,20-dione (the Steroid, Org 6216) and a partially alkylated ~-cyclodextrin.
A partially alkylated ~-cyclodextrin is a deriva-tive of ~-cyclodextrin (or cyclohepta~amylose) in which one or more hydroxy groups are alkylated. Examples of such partially alkylated ~-cyclodextrins are the 2-hydroxypropyl, 6-methyl, 2,3-dimethyl and in particu-lar the 2,6-dimethyl-~-cyclodextrin.
The solubility o~ the Steroid in water increases with increasing concentrations of partially alkylated ~-cyclodextrin until this solubility reaches its level-off phase or maximal level. This maximal level is ob-tained using relatively large amounts of partially alky-lated ~-cyalodextrins, roughly O.2-0.3 mmol. partially alkylated ~-cyclodextrin per mililiter water.
The maximal solubility o the 5tersid in water using 2,6-dimethyl~-cyclodextrin as the solubilizing agent amounts to about 9-10 mg/ml; at this level the 2,6-dimethyl-~-cyclodextrin concentration required is about 0,28 millimol per ml. A further increase of the cyclodextrin concentration contributes less effectively to a further improve~ent of the Steroid's sslubility.
The graph shows the increase o~ the solubility of the Steroid (Org 621~) with increasing 2,6-dimethyl-~-cyclodextrin concentrations.

' ~3~131 The solubility studies were per~ormed according to the method described ~elow which is well known in the litrature. Excess amounts of the Steroid were added to a~ueous solutions of 2,~-dimethyl-~cyclodextrin. These suspensions were shaken at room temperature during 5 days followad by an equilibration period of 3 days at room temperature. Then an aliquot was centrifuged and the supernatant was fil~ere~ t~hrough a 0,45 ~m membrane filter (Millipore: HV4, Millex). The samples were anal-ysed with the Perkin ~lmer Lambda 5 W/VIS spectropho-tometer. The absorbance was read and compared with a blanc and standard calibration curve. ~rom these data the concentration o~ Steroid dissolved in water was cal-culated. After calculation of the amount of Steroid dis-solved, a phase-solubility diagram was constructed by plotting the dissolved amounts of Steroid as a function of the concentratiGn of 2,6-dimethyl-~-cyclodextrin (see Graph).
From the curve obtained the complex stabllity con-stant K was calculated using the formula:
slope K =
SO (l-sloPe) SO = saturation concentration of Steroid without 2,6-dimethyl-~-cyclodxtrin.
slope = the slope of the initial part of the curve.
This complex-stability constant K i5 also a measure for the solubility of the Steroid in water. The higher this complex-stability constant, the better is the sta-bility of the complex and the higher is the solubility in water.
For comparati~e purposes the unexpected increase of solubility of the Steroid in water using 2,6 dimethyl-~-cyclodextrin, is compared with other more common cy-clodextrins. Th~ results are described in the following table:
.
~rad~ - ~ar~

1~0~

Cyclodextrin Steroid reference compounds Org 6216 _ - . 1 ~-cyclodextr~n K (ml.mmol. ) 380 Solubility (mg/ml) 4 x 10-2 R-cylodextriln X (ml.mmol.~ ) 3400 Solubility (mg/ml) 5 x 10 2 r-cvclodextr~ l K (ml.mmol. ) 9600 I
Solubility (mg/ml) 7 x 10 2 Part. alkylated cyclodextrin 2r6~dimethyl~
~aYsal~ I I
K (ml.mmol l) l 58000 Solubility (mg/ml) l 9 Solubility without cyclodextrin, mg/ml l 7 x 10-4 . ~ . - . , I

Besides the essential ingredients Steroid, par-tially methylated ~-cyclodextrin and water, the pharma-ceutical preparation according to the invention may con-tain other active substances and/or pharmaceutical aux-iliaries.
The preparation may optionally contain for example, preservatives, viscosity increasing agents, agents for rendering the solution isotonic, buf~ers for adapting the desired pH, surfac~ants etc., as well as the usual pharmaceutically acceptable carriers and/or diluents.
As already said the preparation according to the invention may be used for all kinds of local administra-tion, e.g. as injection preparation, intranasal prepara-tion, ear-drops, topical preparation (gel, ointment, foam, cream~, but is preferably used for ophthalmologi-cal purposes.
.

6 132~l3l A preparation for local administration is a prepa-ration that i~ locally active and does not exert a sig-nificant systemic effect.
The concentration of the Steroid in the pharmaceu-tical preparation according ~o the invention may vary somewhat depending upon the way of administration. The usual concentration, however, varies between 1 and 10 mg and more par~icularly between 5 and 10 mg per mililiter water. For ophthalmological purposes where usually only one or two drops are applied the concentration of the Steroid i~ preferably as high as possible, viz. about 9-10 mg per ml water.
~xamples 1. ToE~çal qel 2,6-dimethyl-~-cyclodextrin 50,0 g Org 6216 0,9 g pectine 5.0 g sugar 30,0 g water to 100 ml prepare complex, add pectin and ~issolve, add sugar adju~t pH to 3-4.
2. o/w emulslon (w = water phase, o = oil phase) 2,6-dimethyl-~-cylodextrin 185 g w org 6216 3,3 g w sodium laurylsulphate10 g w stearyl alcohol 250 g w white petrolatum250 g w methylhydroxybenzoate0,7 g w propylhydroxybenzoa~e3,7 g w water 370 g w propylene glycol120 g w 1192,7 g prepare oil ph~se and water phase separately at ele-vated temperature~ then, add oil pha~e to water phase and homogenize.

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7 132n~ 31 3. Opthalmic solution (eye drop) Org 6216 4,5 g 2,6 dimethyl-~-cyclodextrin 250,0 g polyvinylalcohol 7,0 g Na2HPO4 3,8 g NaH2PO4 0, 8 g Chlorobutanol 2,5 g NaCl to isotonic Water for injections to 500 ml prepare complex, add other components, adjust to volume.
4. Injectable preparation Org 6216 9 mg 2,6-dimethyl-~-cyclodextrin 500 mg NaOH/HCl to pH 7 Mannitol to isotonic Water for injections to 1,0 ml prepare complex, add other components, adjust to volume.
5. otic ~renaration ~earL
2,6-dimethyl-~-cyclodextrin 125 Org 6216 2,25 g benzylalcohol 10 g sodium carhoxymethylcellulose 0,025 g propylene glycol 25,0 NaCl to isotonic NaOH/HCl to pH 7 Water for injections to 250 ml .

8 1~20131 6. To~ical foam Emulsion base Org 6216 7,1 g 2,6-dimethyl~-cyclodextrin 394,2 g miristic acid 12,6 g stearic acid 42,0 g cetylalcohol 3,9 g lanolin 1,6 g isopropylmyristate 12,6 g triethanolamine 26,3 g glycerin 37,1 g polyvinylpyrrolidone 2,7 g water 7QO,O ml Final 960 g smulsion bas 40 g hydrocarbon propellant A-46 7. Nasal ~reparation - Org 6216 90mg 2,6-dlmethyl-~-cyclodextrin 5000 mg benzalkoniumchloride 0,001 mg EDTA 0,01 mg NaOH/HC1 to pH 7 Mannitol to iæo-osmotic Water for injections to 10 ml ' .
' ' , ~ .

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Claims (4)

1. A pharmaceutical preparation for local administra-tion comprising an aqueous solution of 11-.beta.-hydroxy-16.alpha.,17.alpha.,21-trimethyl.DELTA.1,4-pregnadiene 3,20-dione and a partially alkylated .beta.-cyclodextrin.
2. Preparation according to claim 1 comprising 2,6-dimethyl-.beta.-cyclodextrin as the partially alkylated .beta.-cyclodextrin.
3. Preparation according to claim 1 or 2 especially in-tended for ophthalmological purposes.
4. Preparation according to claim 3 comprising 5-10 mg of the Steroid per ml water.
CA000588137A 1988-01-14 1989-01-13 Aqueous pharmaceutical preparation containing 11.beta.-hydroxy steroids Expired - Fee Related CA1320131C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14388888A 1988-01-14 1988-01-14
US07/143,888 1988-01-14

Publications (1)

Publication Number Publication Date
CA1320131C true CA1320131C (en) 1993-07-13

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CA000588137A Expired - Fee Related CA1320131C (en) 1988-01-14 1989-01-13 Aqueous pharmaceutical preparation containing 11.beta.-hydroxy steroids

Country Status (7)

Country Link
EP (1) EP0326196B1 (en)
JP (1) JPH02706A (en)
AT (1) ATE74003T1 (en)
CA (1) CA1320131C (en)
DE (1) DE68901043D1 (en)
ES (1) ES2037385T3 (en)
GR (1) GR3005035T3 (en)

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ATE100712T1 (en) * 1989-05-24 1994-02-15 Innovet Inc HYPOALLERGENIC ANESTHETIC/HYPNOTIC STEROID MEDICATION.
HU210921B (en) * 1990-03-28 1995-09-28 Chinoin Gyogyszer Es Vegyeszet Process for preparing inclusion complexes of n-ethoxycarbonyl-3-morpholino-sydnonimine formed with cyclodextrines and pharmaceutical compositions containing them
US5494901A (en) * 1993-01-05 1996-02-27 Javitt; Jonathan C. Topical compositions for the eye comprising a β-cyclodextrin derivative and a therapeutic agent
US5977180A (en) * 1994-07-11 1999-11-02 Pate; David W. Anandamide analog compositions and method of treating intraocular hypertension using same
US5631297A (en) * 1994-07-11 1997-05-20 Pate; David W. Anandamides useful for the treatment of intraocular hypertension, ophthalmic compositions containing the same and methods of use of the same
JP2920611B2 (en) * 1995-12-11 1999-07-19 株式会社シーエーシー Topical treatment for dermatitis
US8512718B2 (en) 2000-07-03 2013-08-20 Foamix Ltd. Pharmaceutical composition for topical application
IL152486A0 (en) 2002-10-25 2003-05-29 Meir Eini Alcohol-free cosmetic and pharmaceutical foam carrier
US9211259B2 (en) 2002-11-29 2015-12-15 Foamix Pharmaceuticals Ltd. Antibiotic kit and composition and uses thereof
US7700076B2 (en) 2002-10-25 2010-04-20 Foamix, Ltd. Penetrating pharmaceutical foam
AU2003279493B2 (en) 2002-10-25 2009-08-20 Foamix Pharmaceuticals Ltd. Cosmetic and pharmaceutical foam
US20080138296A1 (en) 2002-10-25 2008-06-12 Foamix Ltd. Foam prepared from nanoemulsions and uses
US7820145B2 (en) 2003-08-04 2010-10-26 Foamix Ltd. Oleaginous pharmaceutical and cosmetic foam
US9265725B2 (en) 2002-10-25 2016-02-23 Foamix Pharmaceuticals Ltd. Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof
US8900554B2 (en) 2002-10-25 2014-12-02 Foamix Pharmaceuticals Ltd. Foamable composition and uses thereof
US7704518B2 (en) 2003-08-04 2010-04-27 Foamix, Ltd. Foamable vehicle and pharmaceutical compositions thereof
US10117812B2 (en) 2002-10-25 2018-11-06 Foamix Pharmaceuticals Ltd. Foamable composition combining a polar solvent and a hydrophobic carrier
US9668972B2 (en) 2002-10-25 2017-06-06 Foamix Pharmaceuticals Ltd. Nonsteroidal immunomodulating kit and composition and uses thereof
US7575739B2 (en) 2003-04-28 2009-08-18 Foamix Ltd. Foamable iodine composition
US8486374B2 (en) 2003-08-04 2013-07-16 Foamix Ltd. Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses
US8795693B2 (en) 2003-08-04 2014-08-05 Foamix Ltd. Compositions with modulating agents
US6960300B2 (en) * 2003-09-08 2005-11-01 Sami Labs Limited Process for preparing water soluble diterpenes and their applications
US20080260655A1 (en) 2006-11-14 2008-10-23 Dov Tamarkin Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses
US8636982B2 (en) 2007-08-07 2014-01-28 Foamix Ltd. Wax foamable vehicle and pharmaceutical compositions thereof
US8432831B2 (en) * 2007-10-30 2013-04-30 Ajou University Industry Cooperation Foundation Method of routing path in wireless sensor networks based on clusters
WO2009069006A2 (en) 2007-11-30 2009-06-04 Foamix Ltd. Foam containing benzoyl peroxide
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WO2009072007A2 (en) 2007-12-07 2009-06-11 Foamix Ltd. Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof
WO2009090558A2 (en) 2008-01-14 2009-07-23 Foamix Ltd. Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses
US20120087872A1 (en) 2009-04-28 2012-04-12 Foamix Ltd. Foamable Vehicles and Pharmaceutical Compositions Comprising Aprotic Polar Solvents and Uses Thereof
CA2769625C (en) 2009-07-29 2017-04-11 Foamix Ltd. Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses
WO2011013008A2 (en) 2009-07-29 2011-02-03 Foamix Ltd. Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses
CN102686205A (en) 2009-10-02 2012-09-19 弗艾米克斯有限公司 Topical tetracycline compositions
US9849142B2 (en) 2009-10-02 2017-12-26 Foamix Pharmaceuticals Ltd. Methods for accelerated return of skin integrity and for the treatment of impetigo
MX2017011630A (en) 2016-09-08 2018-09-25 Foamix Pharmaceuticals Ltd Compositions and methods for treating rosacea and acne.

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DE3346123A1 (en) * 1983-12-21 1985-06-27 Janssen Pharmaceutica, N.V., Beerse PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF
US4686214A (en) * 1985-10-30 1987-08-11 Alcon Laboratories, Inc. Anti-inflammatory compounds for ophthalmic use

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GR3005035T3 (en) 1993-05-24
DE68901043D1 (en) 1992-04-30
ATE74003T1 (en) 1992-04-15
ES2037385T3 (en) 1993-06-16
JPH02706A (en) 1990-01-05
EP0326196A3 (en) 1989-10-04
EP0326196A2 (en) 1989-08-02
EP0326196B1 (en) 1992-03-25

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